. The inhibition of the proteolytic enzyme, HIV protease is still regarded as an attractive therapeutic target for the treatment of AIDS. The clinical effectiveness of the HIV protease inhibitor has been reported recently. However, the major therapeutic limitation is still the presence of a substantial amount of peptide-like character in these protease inhibitors. In recognition of this problem , extensive efforts were made in the areas of peptidominetic design and conformational constraint, however design and synthesis of nonpeptidal small organic molecules thus far has received little attention. In the present study, the investigators' plan is to design and synthesize nonpeptidal high affinity legands as well as small molecules based on the many elegant structure-activity studies and the structural information that are available from X-ray crystal structure of the protein-ligand complexes. An intriguing feature in all reported inhibitor bound X-ray structures in the presence of a tetracoordinated critical water molecule that links the inhibitor to the glycine-rich b-strands (flaps) of the enzyme. This water molecule donates its hydrogen bonds to the appropriately positioned carbonyl oxygens of the inhibitor and accepts two hydrogen bonds from the N-H of Ile 50 and Ile 50' amides of the enzyme. The applicant's nonpeptidal inhibitor design is based on replacing the carbonyl binding to this critical water molecule with appropriately positioned conformationally constrained cyclic ether or sulfone derivatives. The potential application of such molecular mimics is enormous because the polyether molecules of diverse structure and biological activities which abound in nature do not generally suffer the problems inherent to peptides. The specific aims of the present proposal are:(a) to investigate the ability of sterochemically defined cyclic either or sulfone derivatives to mimic the peptide carbonyl binding in the HIV protease substrate binding site.(b) to design and synthesize small molecule (molecular weight < 500 daltons) nonpeptidal HIV protease inhibitors (subnanomolar potency) based on X-ray crystal structures of the protein-ligand complexes and the P. I. and Co-investigator's experience in drug design. All compounds will be evaluated in peptide cleavage assay. Potent compounds will be tested in various cell lines and against patient isolates. Also, they will incorporate important inhibitors in liposomes and investigate the anti-HIV effect of such formulations, particularly in macrophages. Interesting compounds will be prepared in quantities and will be further evaluated at the National Cancer Institute, AIDS program.